This proposal is a part of an integrated project to test the efficacy of three candidate anxiolytics (two structurally unrelated CRr-^ receptor antagonists GSK008 and CRF-002, and a 5HTiA/iB/io receptor antagonist, GSK-1, provided by GlaxoSmithKline (GSK) as part of The Emory-MSSM-GSK-NIMH Collaborative Mood Disorders Initiative, using fear-potentiated startle. The anti-fear and anxiolytic activity of these compounds will be evaluated in healthy subjects using models of phasic (fear) and sustained (anxiety) aversive states derived from humans and from pre-clinical studies in rodents. Two experimental models will be implemented; one based on an instructed fear learning procedure and the other using Pavlovian cued and context conditioning in a computer-generated virtual reality environment, which will also enable us to examine behavioral avoidance. Both procedures are designed to distinguish between phasic fear and sustained anxiety, which according to pre-clinical studies (Dr. Davis, Project 1) are mediated by distinct neural systems. We will examine the potentiation of startle during anticipation of no-shock, predictable shock signaled by a discrete threat cue, and unpredictable shock. Fear-potentiated startle to the discrete threat cue will model phasic fear, whereas the potentiation of startle in the predictable and unpredictable shock conditions will model sustained contextual anxiety. A central goal of this project is to examine whether the GSK compounds are anxiolytic in these models, which have been shown to detect the anxiolytic activity of established anxiolytics (alprazolam, a benzodiazepine, and escitalopram an SSRI). Another goal is to identify different psychopharmacological profiles for phasic fear versus sustained anxiety. Given the prevalence of anxiety disorders in women compared to men, an exploratory aim will be to examine whether sex differences exist with respect to the sensitivity of our anxiety model to treatment with the GSK compounds. These same GSK compounds will also be evaluated in other laboratories (Projects 1 and 5) (separate applications), providing a translational approach to screening and evaluating the efficacy of new compounds. Dr. Davis' preclinical project (Project 1), which is particularly complementary to the present project, will use similar behavioral models in rodents based on startle as an operational measure of fear and anxiety. Drs. Rothbaum and Charney's project (Project 5) will test the clinical efficacy of GSK008 in posttraumatic stress disorder. These parallel projects will provide a test of the predictive validity of the human and animal models. It is hoped that this integrated effort will ultimately lead to development and validation of models for rapid evaluation of novel therapeutics.